Am. J. Respir. Crit. Care Med., Vol 154, No. 6, Dec 1996, 1689-1693.
Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide
HE Fessler, L Otterbein, HS Chung and AM Choi
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Alpha-2 adrenoceptors are widely distributed in vascular and nonvascular
tissue where they mediate diverse physiologic effects. We noted the
laboratory anesthetic urethane, which possesses alpha-2 adrenergic blocking
activity, protected rats against lethal endotoxemia (1). Therefore, we
undertook the present study to examine whether specific alpha-2
adrenoceptor antagonism would protect against lethality and organ injury
induced by lipopolysaccharide (LPS). Sprague- Dawley rats were pretreated
with doses of the alpha-2 antagonist rauwolscine up to 1 mg/kg, followed by
20 mg/kg LPS. The highest rauwolscine dose decreased mortality from 100% to
zero. In contrast, the alpha-2 agonists xylazine or UK 14,304 increased the
lethality of a lower, 10-mg/kg dose of LPS from 20% to 80 to 100%.
Rauwolscine administered after LPS had no protective effect against
mortality. Rauwolscine pretreatment significantly reduced bowel hemorrhage
and liver dysfunction induced by 20 mg/kg LPS, but it had no effect on
hematologic changes, the rise in plasma creatinine, or lung myeloperoxidase
content. Peak tumor necrosis factor-alpha levels were decreased from 1,305
+/- 333 to 493 +/- 155 pg/ml (p < 0.05) in animals pretreated with
rauwolscine. Arterial pressure and heart rate was higher after LPS in
animals pretreated with rauwolscine. We conclude that alpha-2 adrenergic
blockade protects against LPS, either by decreasing tumor necrosis
factor-alpha production or through direct effects on the target tissues of
endotoxemia.
